Nascent structure–activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208

Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual κ/μ opioid receptor antagonist devoid of δ opioid receptor affinity against cloned human receptors: Ki (2)=3.8nM (κ), 30nM (μ); IC50 ([35S]GTPγS binding)=140nM (κ), 21nM (μ). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at κ and μ, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3–10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed Ki values ranging from 14 to 220nM against the κ opioid receptor with μ/κ ratios of 0.45–3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH2 16 and Ac-Phe-trp-Phe-pro-NH2 17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent μ ligands: Ki (16)=340nM (μ); Ki (17)=360nM (μ).